Mutations causing loss of function of bone morphogenetic protein receptor II (BMPRII) are found in familial and sporadic idiopathic (I) pulmonary arterial hypertension (PAH). Reduced levels of BMPRII and its co- receptor BMP-RIa, are observed in IPAH patients without a mutation and in patients with secondary PAH. We will therefore investigate how reduced BMPRII/la mediated signaling is linked to the pathological features in the pulmonary arteries (PAs) that underlie PAH. These features include loss of distal PAs associated with endothelial cell (EC) apoptosis, and progressive narrowing of the lumen of larger PAs related to smooth muscle cell (SMC) proliferation. Based on our novel preliminary findings, we propose that signaling through BMPRII/la regulates the transcriptional activity of peroxisome proliferator-activated receptor (PPAR)y. We hypothesize that PPAR? induces genes that regulate platelet derived growth factor (PDGF)-BB and Wingless (Wnt) signaling pathways. As a result, EC survival, proliferation and migration are promoted and SMC proliferation is suppressed. In the first aim of our proposal we will determine whether BMP2 induces human (h) PA EC survival, growth and motility, by a cooperative interaction between PPAR?- and IJ-catenin mediated transcription of genes. These features prevent loss of vessels in response to injury, and support regeneration. The second aim, investigates how hPA SMC utilize PPAR? mediated regulation of target genes such as apolipoprotein (apo)E to both repress hPA MC proliferation in response to growth factors and to stimulate motility. These features are likely required in repairing vascular injury without obstruction. We will determine whether BMP2 mediated hPA SMC motility requires transcription of (i-catenin targets such as fibronectin to recruit the Wnt pathway protein Dishevelled to the cell membrane to stimulate RhoA-Rad activity. We will also simulate loss of BMPRII function by RNA interference, to determine whether PPAR? agonists can restore hPA EC proliferation and migration, and hPA SMC suppression of proliferation in response to growth factors. Our third aim is to pursue our observation that a transgenic mouse with selective deletion of PPAR? in SMC has PAH. We will determine whether during chronic hypoxia, loss of PPAR? heightens proliferation of SMC and worsens PAH and whether impaired SMC apoptosis impedes regression of PAH upon return to room air. We will also investigate whether a mouse with selective deletion of PPAR? in EC also has severe PAH during chronic hypoxia associated with impaired EC survival and loss of vessels and whether persistent PAH upon return to room air is related to impaired EC proliferation and vascular regeneration. The proposed studies provide mechanistic links between impaired BMPRII/ia function and PAH and may encourage investigation of PPAR? agonists as a treatment option for PAH.